The present technology describes, in general, novel prodrugs/compositions of the stimulant amphetamine (i.e., 1-phenylpropan-2-amine) as well as non-standard amino acid conjugates of amphetamine, salts thereof, other derivatives thereof, and combinations thereof. Additionally, the presently described technology also relates generally to the methods of making and using these new prodrugs/compositions.
The presently described technology in at least one aspect is focused on a slow/sustained controlled release composition of amphetamine, in prodrug form, that allows slow/sustained/controlled delivery of the stimulant into the blood system of a human or animal within a safe therapeutic window upon oral administration. At least some compositions/formulation of the current technology can lessen the rebound effect, cardiovascular stress, addiction/abuse potential and/or other common stimulant side effects associated with amphetamine and similar compounds. Such compositions may also increase the duration of therapeutic efficacy, ease of application, patient compliance and/or any combination of these characteristics when administered, in particular, orally.
Stimulants, including amphetamine and its derivatives, enhance the activity of the sympathetic nervous system and/or central nervous system (CNS) and are prescribed for the treatment of a range of conditions and disorders predominantly encompassing, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and wakefulness.
Attention deficit hyperactivity disorder (ADHD) in children has been treated with stimulants for many years. However, more recently, the increase in number of prescriptions for ADHD therapy in adult population has, at times, outperformed the growth of the pediatric market. Although there are various drugs currently in use for the treatment of ADHD, such as methylphenidate (commercially available from, for example, Novartis International AG (located in Basel, Switzerland) under the trademark Ritalin®) and non-stimulant atomoxetine (commercially from Eli Lilly and Company (located in Indianapolis, Ind.) as Strattera®), amphetamine has been the forerunner in ADHD therapy. Moreover, during classroom trials non-stimulants have shown to be less effective in improving behavior and attention of ADHD afflicted children than amphetamine derivatives.
Initial drug therapy for ADHD was limited to fast acting immediate release formulations of stimulants (e.g., Dexedrine®, pure dextroamphetamine sulfate, commercially available from Smith Kline and French located in the United Kingdom) which triggered an array of potentially undesirable side effects including, for example, fast wear-off of the therapeutic effect of the stimulant active ingredient causing rebound symptoms, cardiovascular stress/disorders (e.g., increased heart rate, hypertension, cardiomyopathy), other side effects (e.g., insomnia, euphoria, psychotic episodes), addiction and abuse.
Behavioral deterioration (rebound/“crashing”) is observed in a significant portion of children with ADHD as the medication wears off, typically in the afternoon or early evening. Rebound symptoms include, for example, irritability, crankiness, hyperactivity worse than in the unmedicated state, sadness, crying and in rare cases psychotic episodes. The symptoms may subside quickly or last several hours. Some patients may experience rebound/crashing so severe that treatment must be discontinued. Rebound/crashing effects can also give rise to addictive behavior by enticing patients to administer additional doses of stimulant with the intent to prevent anticipated rebound/crashing negative outcomes and side effects.
Stimulants, such as methylphenidate and amphetamine, have shown to exhibit noradrenergic and dopaminergic effects that can lead to cardiovascular events comprising, for example, increased heart rate, hypertension, palpitations, tachycardia and in isolated cases cardiomyopathy, stroke, myocardial infarction and sudden death. Consequently, currently available stimulants expose patients with pre-existing structural cardiac abnormalities or other severe cardiac indications to even greater health risks and are frequently not used or used with caution in this population. It is notable, however, that the cardiovascular effects of stimulants, for example on heart rate and blood pressure, is dependent on the administered dose. As a result, a treatment which maintains the lowest effective stimulant blood concentrations for a therapeutically beneficial duration is believed to demonstrate fewer cardiovascular risks.
Amphetamine and many of its derivatives (e.g., methamphetamine, 3,4-methylenedioxy-methamphetamine/“Ecstacy”) are widely abused for various purposes such as euphoria, extended periods of alertness/wakefulness, or rapid weight loss or by actual ADHD patients who developed excessive self-dosing habits to prevent rebound symptoms from manifesting, for example, in anxiety or depression. The effects desired by potential abusers originated from the stimulation of the central nervous system and prompted a Schedule II or even Schedule I classification for amphetamine (d- and l-amphetamine individually and any combination of both are Schedule II) and certain derivatives thereof after passage of the Controlled Substance Act (CSA) in 1970. Both classifications are defined by the high propensity for abuse. Schedule II drugs have an accepted medical use while Schedule I substances do not pursuant to the CSA. So far, all amphetamine products, including compositions with sustained release formulations and prodrugs thereof, are obligated to include a black box warning on the drug label to inform patients about the potential for amphetamine abuse and dependence.
It has been shown in the conventional art that most side effects of amphetamines are caused by a large initial spike in blood concentration of the stimulant which quickly erodes to levels below therapeutic effectiveness (typically within 4-6 hours). As a consequence, the high potency of dextroamphetamine (d-amphetamine) was subsequently modulated by a series of new drugs with increasingly sustained release profiles achieved by delivering amphetamine more slowly into the blood stream with the goal to create safer and less abusable treatment outcomes and regimens. The methods and technologies for generating smaller spikes in drug blood concentrations include, for example, use of mixed salts and isomer compositions (i.e., different salts of d- and less potent l-amphetamine), extended/controlled/sustained release formulations (e.g., Adderall X® commercially available from Shire U.S., Inc. located in Wayne, Pa.) and, most recently, prodrugs of amphetamine (Vyvanse™ also commercially available from Shire). The ideal drug treatment option should produce stimulant blood concentrations within a narrow therapeutic window for an extended time duration followed by a prolonged fade-out period in order to minimize cardiovascular stress and behavioral deterioration, and would also exhibit anti-abuse properties.
Besides immediate release formulations, newer sustained release formulations have been developed with the objective to provide a therapeutic treatment option that offers the convenience of a single daily dosing regimen versus multiple quotidian administrations. Such formulations also have the objective of imparting or rendering a euphoric response. Sustained release formulations commonly consist of drug particles coated with a polymer or polymer blend that delays and extends the absorption of the active drug substance by the gastrointestinal tract for a relatively defined period of time. Such formulations frequently embed the therapeutic agent/active ingredient/drug within a hydrophilic hydrocolloid gelling polymer matrix (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose or pullulan). This dosage formulation in turn becomes a gel upon entering an acidic medium, as found in the stomach of humans and animals, thereupon slowly effusing the therapeutic agent/active ingredient/drug. However, the dosage formulation dissolves in an alkaline medium, as found in the intestines of humans and animals, concurrently liberating the drug more quickly in an uncontrolled manner. Some formulations, such as acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, and hydroxypropyl methylcellulose phthalate, offer improved sustained release in the intestines by being resistant to acidic environments and dispensing the active ingredient only at elevated pH via a diffusion-erosion mechanism, either by themselves or mixed with hydrophilic polymers.
Sustained release formulations have been moderately effective in providing an improved and extended dosage form over immediate release tablets. Nonetheless, such formulations are potentially subject to inconsistent, erratic or premature release of the therapeutic agent due to failure of the polymer material and they also usually allow easy extraction of the active ingredient utilizing a simple physical procedure. Since single daily dose formulations contain a greater amount of amphetamine than immediate release formulations, they are more attractive to potential abusers, consequently making the extractability of drug substance an additional undesirable property. It is also, at least in part, a reason for increased drug diversion, especially evident by selling or trading of medication by school children who are ADHD patients and in possession of sustained release amphetamine capsules. The obtained stimulants are then abused by classmates without the disorder by either ingesting high doses or snorting the drug material after crushing it.
U.S. Pat. No. 7,105,486 (to assignee New River Pharmaceuticals, hereinafter the “'486 patent”) appears to describe compounds comprising a chemical moiety (namely L-lysine) covalently attached to amphetamine, compositions thereof, and methods of using the same. Allegedly, these compounds and their compositions are useful for reducing or preventing abuse and overdose of amphetamine. The '486 patent also describes that using any amino acid other than l-lysine (Table 46) will not give rise to the same in vivo properties demonstrated by l-lysine-d-amphetamine (Lys-Amp, Vyvanse™). Additionally, since lysine is a natural and standard amino acid, the breakdown of the new prodrug occurs faster than desired to reduce the side effect profile. Thus, quick release of amphetamine from such standard amino acid conjugate compositions may cause an increase in blood pressure and heart rate found in other conventional stimulant treatments. As a result, there still exists a need within the art for a safer dosage form of amphetamine, and treatment regimen that is therapeutically effective and can provide sustained release and sustained therapeutic effect